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AAV-Based Gene Therapies at Our Doorstep: Understanding How They Work

  • Authors: Francesco Muntoni, MD; Benedikt Schoser, MD
  • CME Released: 4/26/2023
  • Valid for credit through: 4/26/2024, 11:59 PM EST
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Target Audience and Goal Statement

This educational activity is intended for an international audience of non-US pediatric neurologists, neurologists, neuromuscular disease specialists, pediatricians, and primary care physicians.

The goal of this activity is for learners to be better able to explain gene therapy, its expectations, and how it is implemented, highlighting the role of AAV vectors.

Upon completion of this activity, participants will:

  • Have increased knowledge regarding the
    • Advantages of using AAV-based vectors for gene therapy
    • Mechanisms by which AAV vectors enable cellular transduction and express a functional transgene
    • Potential risks associated with AAV-mediated gene therapy


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  • Francesco Muntoni, MD

    Professor of Paediatric Neurology
    Director of the Dubowitz Neuromuscular Centre
    UCL Great Ormond Street Institute of Child Health
    London, United Kingdom


    Francesco Muntoni, MD, has the following relevant financial relationships:
    Consultant or advisor for: Biogen; Novartis; PTC; Roche; Sarepta
    Speaker or member of speakers bureau for: Biogen; Novartis; PTC; Roche; Sarepta
    Research funding from: Biogen; Roche; Sarepta
    Other: Board Membership: Dyne Therapeutics; Pfizer, Inc. Therapy development for: DMD

  • Benedikt Schoser, MD

    Professor of Neurology
    Department of Neurology
    Ludwig-Maximilians-University of Munich
    Munich, Germany


    Benedikt Schoser, MD, has the following relevant financial relationships:
    Consultant or advisor for: Amicus Therapeutics, Inc.; argenx; Astellas Pharma, Inc.; Bayer; Maze; Sanofi
    Speaker or member of speakers bureau for: Alexion Pharmaceuticals, Inc.; Kedrion; Sanofi
    Research funding from: Amicus Therapeutics, Inc.; Astellas Pharma, Inc.


  • Grace O’Malley, BSc, PhD

    Associate Medical Education Director, WebMD Global, LLC


    Grace O’Malley, BSc, PhD, has no relevant financial relationships.

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  • Leigh Schmidt, MSN, RN, CNE, CHCP

    Associate Director, Accreditation and Compliance, Medscape, LLC


    Leigh Schmidt, MSN, RN, CNE, CHCP, has no relevant financial relationships.

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This activity has been peer reviewed and the reviewer has no relevant financial relationships.

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AAV-Based Gene Therapies at Our Doorstep: Understanding How They Work

Authors: Francesco Muntoni, MD; Benedikt Schoser, MDFaculty and Disclosures

CME Released: 4/26/2023

Valid for credit through: 4/26/2024, 11:59 PM EST


Activity Transcript

Francesco Muntoni, MD: Hi, I'm Francesco Muntoni, from University College London. I welcome you to this program entitled "AAV-Based Gene Therapies at Our Doorstep: Understanding How They Work." Joining me today is Professor Benedikt Schoser from the Department of Neurology, Ludwig Maximilian University of Munich, and Benedikt will introduce himself now and start with the first part of this program.

Benedikt Schoser, MD: Thank you Francesco for this very kind introduction, and of course doing this program together with you is my pleasure. Gentlemen and ladies, I'd like to start to give you a bit more background first, and then we come in the discussion perhaps more to details.

First, we have to discuss the things about the different types of gene therapy approaches. There are 3 elements. Normally there could be a gene addition, there could be a gene silencing, and a gene editing. What is meant by this? Gene editing is something that corrects pieces of the DNA by changing or deleting information within the affected individual's gene. That's the most common part and most interesting part for us.

What is gene silencing doing? Here a delivered genetic material prevents or inhibits the activity of a gene that is already present in the cell, often decreases the amount of a specific protein that's being made. And by gene addition or editing, is the adding in a working gene that has the instructions for the cell to make more or a specific protein that is needed. These are the key 3 elements we have to discuss.

So, how will this work? In brief, we have some additional possibilities for packing material and transmitters to different cells. And we have some common working horses -- so, the adenovirus, or adeno-associated virus (AAV), and there's lentivirus systems, and also there's a herpes simplex virus system -- those are the ones we use. Today, we will very much focus on the adeno-associated virus, because that's the most handsome guy here in this context.

What are the viral vector components? Of course, we have something that is called "capsid," or the envelope of a virus, that is containing genetic material and determining the cell tropism or specificity of the target we want to reach. And then, of course, we pack into this the transgene of interest. And this is flanked in a way by a "regulatory cassette" here -- elements controlling the on and offs of the transgene expression. Very important things, and I will come to this later on.

If we look at a gene replacement therapy, this relies on the use of a vector based on a virus such as the AAV to potentially deliver the corrected gene to the target cell. So, it can be targeted specifically to cell types via the type of AAV we are using. Or it can be done by, in addition, can be done by tissue-specific promoters that drive expression to a human functional protein in the target cells. So, this is sometimes subdivided, and the topic will come to this, we come to this later on. If it's muscle targeted, that's our key interest, or it could be targeted to the liver, or it could be targeted to the heart, and of course to neurons as well. And this is very important because gene replacement therapies are being developed of a potential treatment of all these type of cells, and therefore we need sometimes these tissue-specific promoters and the cell types, they're very specific for the AAV virus. This is very important to start with this.

So, how is now the transfection done? How can we get a virus packed with a transgene into a cell? First of all, it's this particle, this transgene, and the vector is recognized by glycosylated cell surface receptors. Here it's taken up, the vector is taken into the cell via the endosomes, then the endosome breaks down, and then a very important step comes: the nuclear pore entry and the uncoding of the therapeutic DNA that enters the cell nucleus. In the cell nucleus, the DNA forms a double-stranded circular episome, and this is now ready for the transcription.

The transcription happens, and mRNA transcription focused then pointing out into resulting a transcription that migrates to the cytoplasm for the translation. And finally, the functional proteins synthesis will happen, and then the circle can be repeated and will be repeated in different cells. It's a very important and rather easy, in a way, mechanistic approach for how a functional protein synthesis is given to a gene replacement therapy. This is very important mechanism.

And, of course, I think at this step I hand over to my dear colleague, Francesco Muntoni. He will give us some more details on the natural serotypes and the tropisms we want to consider for our treatments. Francesco.

Dr Muntoni: Alright Benedikt, thank you. I think that was very helpful and a useful introduction to what I have to say because, as Benedikt mentioned, the capsid of the AAV dictate[s] to some extent the fade of these AAV vectors. And in this slide you will see the number of AAV-based therapy capsid[s] that have been used and where they derive [from]. For example, there are in this table between AAV1 and AAV12. And then you can see where these have been originally isolated; these AAVs, for example, some in the monkeys, some in the human[s].

Interestingly, and to complement what Benedikt mentioned, in this table you realize that the primary receptor and the co-receptor of each of these AAVs is different, and therefore is not a surprise that these different AAV[s] have a different biodistribution in the human[s]. And towards the right-hand side you will see the tropisms: the preferential tropisms. I think [it] will be fair to say that no AAV so far only does one single thing in a single cell. But I think that because of the receptor, there is a preferential targeting in different human tissue.

And in this subsequent slide, you have an example of how this different tropism and these different AAV vectors have been used in neuromuscular and neurological trials, and there are a number. These are studies ongoing, completed. And there are clinical trials on delivering AAV to [the] brain. And take the example of the first one; this is a mucopolysaccharidosis type IIIA. This was an AAV9 vector that is delivered intravenously. Then you move down that list and in amyotrophic lateral sclerosis (ALS), a gene therapy for SOD1 will be delivered intrathecally. And I think so you move down the list and realize how many gene therapies are at the moment in clinical trial, with the one, which is the green one, for spinal muscular atrophy that has already been approved and is approved in most of the Western countries. And you have which serotypes have been used in these different types of intervention.

The next 2 slides dwell a little on what is an emerging aspect that is as important as ensuring that AAV gene therapy, of course, works and delivers an effective transgene and make[s] patient[s] better. But there are, of course, aspects related to the high viral low loads that are used in this AAV that are important to be acknowledged, recognized, because if unrecognized, they may lead to significant adverse event and vice versa. If you know what you're looking for, you can help to ensure optimal outcome. And I think that this particular slide is just an example of how it's important to ensure that the patient, for example, has not been previously exposed to AAV because, or to the AAV you want to use, because otherwise this may lead to adverse event, but also may lead to transgene to be not able to deliver the gene you want to this patient.

And then there are toxicities that are better described in the subsequent slide related to the innate immunity and adaptive immunity. Let me take you through what are the examples of when there could be this event and when you need to look after them. In general, while I'm not aware of a problem that has occurred on the day of the inclusion, acute events, meaning immediate events, have not been described yet. However, pain infusion events in the first week, they are common. Some are pretty generic, for example, the nausea, vomiting, fever, malaise, is probably not a complete surprise because they're giving a high number of viral particles.

In the first 2 weeks, the innate immunity may start to be prevalent, and this will be like the early humoral response against the viral capsid protein. At the most severe end of the spectrum, you could have, luckily very rarely, thrombotic macroangiopathy, and this will be associated often with low platelets and eventually kidney injury. More frequently, there are low platelets, there will be injury, and some heart muscle potential involvement as a result of this immunity. Not necessarily is this a paralyzing fear, but at the same time there are things you can check to ensure your patient is not going into one of those directions because as we discuss later on, there are things you can do.

In the first 3 months, the innate immunity then will disappear and, really, the most important adverse event that we now recognize -- won't be present in all, but it is not uncommon -- is liver inflammation. And this is now immune response against the viral capsid, but this is now T-cell mediated. And then, depending on the type of transgene you use and the genotype of the patient -- if the patient is completely absent for a particular protein, this may be relevant -- there may be, therefore, in some patient[s] the recognition that the protein you put there is a foreign protein.

So, I think this gives a summary of the things to look for, and I think we now can move into, if you like, exchange of experience between Benedikt and myself. I think that perhaps I will kick off the discussion with Benedikt and ask, what makes AAV gene therapy different from any other approach you have been involved with?

Dr Schoser: Thank you Francesco for this really wonderful second part of the introduction. I think [it is] very important to raise very important points.

Yeah, for your question, one of the key differences we see is we want to have a continuous expression of our transgene, and AAV is a rather handsome model to work with. Therefore, we can unpack a lot of different information, and what you listed, you see in how many different diseases it's now used. So, this speaks that it's doable, that we can exchange information, transmit them into this capsid, and transfect our target cells in the right way. Therefore, this is why it's so, so common now using AAV vectors and not the other ones because they have more trouble.

There's one element I'd like to point out here. At least what we know today is that there is hardly any genomic integration, and that is one of the big differences for AAV compared to lentivirus and others. Also, there might be some, but it's still only limited. This is some very helpful element for us in the treatment of our especially very young patients. That's the key target we have as early as we treat, as better we might treat. So, therefore, this AAV is something of high interest over the past 10 years now. We're learning patient by patient new information in addition.

But, Francesco, what are the typical diseases or gene defects we treat? You listed a little of them, but what is the key interest you are in?

Dr Muntoni: There are these lower-hanging fruit, then there are more complex aspects. Theoretically, you could treat different type[s] of conditions. I will make a few specific examples. But traditionally, there are limitations regarding how much you can put into this transgene. But more importantly, it's easier to deal with recessive conditions because the replacement of the defective gene restore what the patient is unable to produce. Typical example is spinal muscular atrophy as probably one of the most diffused example[s]. I believe there are several thousand people treated worldwide in the real world now with that. That is a typical example.

This is not to say that AAV gene therapy would not be amenable to treat more complex pathogenesis, and I take the example of the dominant mutation causing ALS in SOD1, where AAV gene therapy has been used, but this time not to re-express the defective gene, but to silence the mutant allele. I think potentially, therefore, also dominant diseases are amenable. However, I think it would be fair to say that of the list that I showed, that there are around probably 98% of those examples are recessive, because I think for a variety of reason[s] they are the complications are much reduced in the recessive disease.

But I alluded briefly to the size, but I didn't dwell on the size because I think this is an important aspect. Again, in clinical trial[s], which you have either been involved or you are aware of the neuromuscular disorder, what are the implications of the size of the transgene that can be used?

Dr Schoser: Yeah, that's an important [aspect]. So, the packing capacity of the virus -- this is always what we are looking at and interested in. We know that this is one perhaps really clear limitation what we have for the AAV virus: that our capacity on transgenes we can put in is limited. But here at least for many of the recessive genes, and even if you now consider Duchenne as an X-linked treatment, we have now methods where we look for sequences and parts of the sequences. These are highly important, and there are other flanking sequences you can even delete or get rid of it, so that you can microgene transmit into it, and that's one of the approaches currently done for Duchenne, where we have now a microdystrophin that gives rise to a working protein in the cell. So therefore, this will overcome some of the situation because as many of our even recessive genes are already really large gene[s]. Think about titin, think about nebulin, all these structural myopathy genes we would love to treat. Those are the giants. That's even given by the name of some of them. Here we hardly can pack the full gene into an AAV vector. We have to downsize it to the core elements and look how good it works.

For others, it's completely helpful. So, for Pompe disease, you can pack the full GAA gene into a vector, and this can then be fully transmitted. It will be an adaptation gene-by-gene, disease-by-disease, but we have now the tools to do that. That's perhaps the difference of looking back 5 or even 10 years' time. So, that's one of the parts.

Coming to the next question here, can anyone receive gene therapy, Francesco? Do you think this is our future, even for us getting older and there might be some diseases we want to get rid of? Are we kept able to have gene therapy in future for whatever? Prostate cancer would be something perhaps as males we can face, things like that.

Dr Muntoni: Thank you for reminding me we are getting older. Can anyone receive gene therapy? I think the reality is probably not, for a few reasons. And I will just go through a few that come to my mind. The most obvious one is the fact that [one] may have already been in touch with that particular AAV serotype in the past.

The other aspect relates to the fact that there may be specific comorbidities. I make an example. We know now, unfortunately, from issues that have occurred in some of the clinical trials that having comorbidities... I make an example: Say that an individual has a chronic liver involvement. Well, to induce damage in that liver by the AAV gene therapy may be tipping the pathology process too far. Similarly, if you have already advanced cardiac involvement, I think we are really finding what are the boundaries of what is safe and not safe if you have preexisting comorbidities of significance, of course.

I think the only other one that I can think of that I have encountered as well is to be sure that at the time you're ... even in an individual without this complex structural or additional comorbidities. I'm a pediatrician so most of my patient[s] would be children, and therefore, children, viral infection, and so on, they not un-often, not rarely, come together. So ensure that at the time you are administering the gene therapy, the child has not been exposed to another viral infection -- that is useful. Also, we have some intervals between giving vaccination, especially a live vaccination, and the ability to do a gene therapy.

But I think apart from that, it is clear. I think, again, example in the spinal muscular atrophy is probably the ... just because it's one of the most used one at the moment in the neuromuscular field, the majority of the people you see are able to receive the gene therapy.

The question that is linked to some of what you said earlier on, Benedikt, the fact that this is a non-integrated vector, this comes with advantages when it comes to safety, and it comes with potential disadvantage depending on that target organ. Can one administer AAV gene therapy multiple times, and what are implication[s] perhaps for different issues or different diseases?

Dr Schoser: Yeah. That's indeed something we have now to consider right at the beginning of the start, in a way, of any new clinical trial; to consider that the stability of our transgene and of the plasmid is not lifelong. Of course, it is our hope. But we see already -- and we look at hematology because they are up to 10, 15 years ahead of us -- so therefore, we know a bit about this. But also, blood is a completely different tissue compared to what we are dealing with, neurons and peripheral nerves, and muscle.

But anyhow, currently, we have not something completely in place. We have some thoughts how we can do re-treatment. Currently, if you have been administered with an AAV gene therapy, you will normally develop highly sustained antibodies against the virus capsid: so any type of AAV, you will have AAV2, AAV8, AAV10 high titers. Therefore, you would be considered as untreatable or not inclusive for any new treatment, but also not for a repeated second dose because your immune system, as you laid out very well, has different parts that will overcome this new treatment action and will dim down the efficacy of really this type of treatment.

But as we learned, of course, and we know from other autoimmune diseases, there are options to do it. It might not be first line now currently with the pharmacological drugs, but this will come as well. But currently, immunoabsorption or plasmapheresis and things like that could bring down the virus titers to nearly normal, so that a re-treatment would be possible in exceptional cases. We will face this rather soon, I guess.

One of the latest developments here is the neonatal Fc receptor inhibitor blocking drugs. That could be perhaps an even newer [development]. And even our steroids would come here in line with some of these. So therefore, there might be ways and we have to do it in a clinical trial to see how we can bring that down and if we find a specific time window where we can re-treat. And along with this re-treatment, what we have to do on immunosuppression during this phase as well.

By coming this, Francesco, I'd like to challenge you a bit more on this. What do we know currently about the percentage of seropositive patients of different AAVs at especially different ages? I think that is something: the range of AAV vector percentage during age might change and might be a hurdle for a first-time treatment with AAV vector therapy.

Dr Muntoni: Thank you. This is a very relevant question, and of course, it is a moving target because we are testing more and more patients in different groups, not only in different... So, there have been previously studies, for example, in the States regarding different serotypes. But in Europe, these studies are only been emerging for the last few years, and we know much less regarding [it]. Most of the study been done in the Caucasian population, so I think that this is something that may well have regional variation. So, it's a bit difficult to give a general figure.

I can say that for some of the AAV gene therapy trials where perhaps we know better, for example, AAV9 for spinal muscular atrophy, the number of children who are ineligible in the first few months or year of life is very small, certainly below 10%. However, if you then move into some of the trials recruiting people in the teens, for example, with AAV9, there are different frequencies of AAV positivity, for example, in the States and in Europe, with some countries in Europe having already nearly 40%, 50% of people in their teens who have been already exposed to AAV9.

This is an issue that is being characterized more and more now that there is a particular reason to do this, and I think is one that we'll need to grapple with. And I think, as you said, there is ongoing work to try to consider the re-administration of AAV, but of course, after gene therapy, that is challenging because the viral load that is given is immense during the AAV gene therapy. But for the natural exposure to AAV, the antibody targets is very different. I suspect it would be easier to administer an AAV with appropriate treatment to somebody who has been just naturally exposed and has got mildly to moderately elevated AAV titer as opposed to somebody who have previously received AAV gene therapy, but little-by-little we will hopefully be there.

I think that if we move now to some of the practicalities, what is the process for gene therapy at your site? Is this done in a specialized unit, is it in an intensive care unit, is it done in an outpatient room? How do you do it?

Dr Schoser: Well, of course we don't do it in a very specialized unit. We do it at our inpatient unit, because we think for at least the first 24 hours, it's good to have the person very close by. But well, the way we had to be established how to do this because we have, of course, the material be prepared at the pharmacy, then it will be on the special transport, like for chemotherapies, very similar approach we have, so we have a standard operating practice in place. And then after 24 hours, we normally leave the patients out to our outpatient clinic. So, they will join in for another blood drawing and things like that over the next days, but then they will move to home. That's really the way and I think it will be very similar in your unit.

Dr Muntoni: The process a little bit has been moved from intensive care unit to the clinical research facility, where there is a confined, in a single room where you are in control. Although AAV is a pretty safe thing, there are infection control regulations that suggests that the control[led] environment, that the minimal barrier is necessary. So, I think for us now, the clinical research facility offers that possibility.

Dr Schoser: We're talking about this, so what type of complications perhaps have [you] yourself seen and what are the ones that might arise?

Dr Muntoni: I think that some complications are very common and they're not very severe. But having said that, as we do not deal with people who do not have a disease, there still are adverse event[s] of special interest, I would say. And I will make the example of nausea and vomiting, especially in people with Duchenne muscular dystrophy. The reason why I'm saying this is that as you know, the people with Duchenne muscular dystrophy will be, in addition to receiving these steroids as a result of this, under chronic corticosteroids.

But if people start to vomit and [can]not keep down the corticosteroids, that has 2 additional problems. One is that the immunosuppression we want for the patient receiving the AAV gene therapy is gone. And secondly, these people are chronically adrenal suppressed, and therefore, they cannot mount the physiological adrenal axis response to even a moderate stress. So, I think we are particularly careful into this. I have to say very rarely this is an issue. But I think if untreated, that would be quite nasty. So, that empowers us as doctors to do something useful.

The second thing we look into with quite a lot of detail, I haven't personally ever observed a thrombotic microangiopathy, and touch wood I will not get exposed to that, but at the same time, we are mindful of the fact that this potentially could occur, and therefore we really religiously monitor the patient in the first 2 weeks for dermatological aspects to look for red blood cell crenation and other aspects that may suggest incipient, because that I think is the quest. The key word is incipient. When you're dealing with this problem at the very beginning, they are much easier to deal with.

Then, of course, the liver involvement, that is well known. It does occur. And I think that we recognize now there are at least 2 phases. An early liver involvement that's probably more related to the early innate immunity, and this appears to respond usually quite well to corticosteroids, but depending on the severity, we use different regime[s] of corticosteroids in many of the clinical trials. This is very well explained. And in my experience, this responds quite well to steroids. And I'm not aware of anybody ever having, ever going into acute liver failure as a result of this problem. I think that there may then be the second wave that is more chronic and I think often responds to corticosteroids, but the response to corticosteroids may be less immediate and with some patient requiring quite chronic corticosteroids. Again, this happens rarely, but at the same time, these are the times when you can do something for your patient.

I think that I haven't experienced any problem related to [the] heart. Sometimes troponin is mildly elevated in multiple problems. We really do not understand it, but I think from my perspective, provided that the patient has a good cardiac function, we will monitor it, but I am not aware at the moment of any patient who had a good cardiac function at pre-screening who ended up having a big problem after AAV gene therapy for any of the neuromuscular disorders. But from there, not to check, that's different, so we've checked, but so far, and the literature suggests, that unless you have substantial cardiomyopathy where a lot of attention needs to go, then I think I've not so far seen anything particularly concerning, nor read something particularly concerning on that front.

There is, again, a particular attention to those patients who are CRIM negative, meaning they have complete loss-of-function mutation with no production of that particular protein whatsoever. I think in these patients, certainly in Duchenne this occurs very rarely, but there has been some cases where individuals with Duchenne have quite a violent response to the AAV gene therapy, with an additional really immune rejection of the transgene.

Again, with time, we are learning which are the genotypes that if you have some residual protein expression, that really helps. And that, to some extent, has helped with spinal muscular atrophy field, because with all people with spinal muscular atrophy having SMN2, they're never CRIM negative. But in some conditions and different mutations this probably needs to be looked at with a little more care.

One question I have just to conclude this round of questions is one particular and quite unique aspect of gene therapy. You briefly indirectly alluded [to] before, but I think it's probably important to stress it again, both for our colleagues but also for families. If you have an individual who has had gene therapy for any of the conditions you deal with, could this individual be recruited in another clinical trial, not necessarily an AAV gene therapy trial, but another clinical trial moving forward?

Dr Schoser: Yeah, it's a very good question, because we will face this in future, I think. Currently, there is already some ongoing, but it's gene therapy done by AAV vector and combined with antisense oligonucleotide treatment. But at least to my knowledge -- but I have a limited knowledge, so therefore I know I have some caveats here -- I'm not aware that someone started to give 2 different types of vectors to one person so far. I don't know, might be someone around, but not to my knowledge, and I would consider this currently.

The obvious question is why can't we combine AAV2 with 8 and 9, and bring it all in together and targeting a lot of organs in the same time? Well, I would consider that then we have really a high impact on our immune system, and I would guess that the body will react very heavily against this type of invasion; therefore, no one has really done this work. But it could be a future consideration if you had perhaps an AAV8 treatment and now you have done a course of immunoabsorption, that you then start your re-treatment with a different serotype of the vector. That could be something I could consider.

Dr Muntoni: I think it is only at the time of the consent, there are some specific aspects to mention to families, that having been involved in a gene therapy trial may preclude -- may, not will -- but may preclude participation to future clinical trial[s], because we do not know what's included criteria of the other clinical trials that will come are. I think that is something that we certainly find.

Dr Schoser: Definitely. I think, Francesco, we could go on here another hour to discuss a lot of extra points. It's always very nice for me, a good learning discussing with you. There's always new aspects. Therefore, thank you for joining me here for this approach to tell our colleagues a bit more what's currently ongoing, and what are the different types of aspects, and about the AAV vector. But we have to thank now the audience for their participation in this activity, and please, audience, you're more than welcome to answer questions, and questions that will follow.

This transcript has not been copyedited.

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